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Abstract

Background: Although induced pluripotent stem cell (iPSC) is a promising candidate which induces cardiomyogenesis in the failing heart, its clinical application is concerned with teratoma/tumor formation from undifferentiated iPSCs contaminating in the graft. We herein hypothesized that an antibody-cytotoxic drug conjugate which targets a specific antigen on undifferentiated iPSC membrane may eliminate residual undifferentiated cell fraction, resulting in avoidance of teratoma/tumor formation in vivo.

Methods and Results: Comprehensive flow cytometry analysis identified a consistent expression of CD30 in the undifferentiated human iPSCs (87.7±9.2%), but rarely in the cardiomyogenically differentiated iPSCs. Addition of anti-CD30 antibody-drug conjugate (brentuximab vedotin), which is clinically used for lymphoma therapy, in vitro for 72 hours efficiently induced cell death in human iPSCs (3.3±0.4% survival) associated with increase in the ratio of G2/M phase (from 9.3±1.1% to 17.1±2.3%), but failed to affect survival of the normal human dermal fibroblasts (99.7±0.3% survival). In addition, percentage of Annexin-V positive cells after the brentuximab vedotin treatment was significantly higher in the human iPSCs (71.5±10.9%) than that in the human fibroblasts (2.8±0.6%). Moreover, the brentuximab vedotin treatment significantly reduced expression of Lin28, an undifferentiated cell marker, in the cardiomyogenically differentiated human iPSC preparation (39±26% reduction compared to untreated cells). Transplantation of untreated human iPSC-derived cardiac tissue into the NOG mouse consistently induced teratoma/tumor formation with a substantial number of Ki-67 positive cells in the graft (240.8±27.9 /mm2) at 16 weeks post-transplant (n=6), whereas that treated with brentuximab vedotin prior to the transplantation failed to induce teratoma/tumor formation, associated with absence of Ki-67 positive cells in the graft over the same period (n=8).